The present invention relates to new indoline compounds having 5-HT2c antagonist properties, to a process for their preparation and to pharmaceutical compositions containing them.
5-HT2c receptors exert inhibitory control over dopaminergic and noradrenergic transmission (Neuropharmacology, 1997, 36, 609, J. Psychopharmacol. 2000, 14 (2), 114-138). 5-HT2c antagonists are accordingly considered to be useful in the treatment of numerous pathologies of the central nervous system (CNS). There may be mentioned, without this list being entirely exhaustive, disorders such as anxiety (Br. J. Pharmacol., 1996, 117, 427), depression (Pharmacol. Biochem. Behav., 1988, 29, 819-820), impulsive disorders (Biol. Psych., 1993, 33, 3-14), sexual dysfunctions (J. Pharmacol., 1997, 11, 72), Parkinson""s disease (Drug News Perspect., 1999, 12, 477), migraine (Life Sci., 1994, 54, 641-644), cognitive disorders (Neurosci. Biobehav. Rev., 1999, 23, 1111-1125), sleep disorders (Neuropharmacology, 1994, 33, (3/4), 467-471), schizophrenia (Neurosci. Lett., 1996, 181, 65) and appetite disorders such as bulimia and anorexia (British J. Pharmacol., 1998, 123, 1707-1715).
The present invention relates to new indoline compounds which differ from the compounds of the Applications WO 9529177 and WO 9748699 not only in the absence of a pyridyloxy substituent on the 3-pyridylaminocarbonyl group of the indoline but also, especially, in the presence of a benzo group fused to the indoline group.
Surprisingly, those structural changes provide the compounds of the invention with pharmacological activities that are clearly superior to those of the compounds of the Applications WO 9529177 and WO 9748699. The compounds of the invention have been found, especially, to be very active by the oral route.
Use of the benzoindoline radical in the compounds of the invention has accordingly made possible a remarkable improvement in the pharmacological properties.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
R1 and R2 together form a benzo ring optionally substituted by a halogen atom or by an alkyl, alkoxy, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino or trifluoromethyl group, and R3 represents a hydrogen atom, or
R1 represents a hydrogen atom, and R2 and R3 together form a benzo ring optionally substituted by a halogen atom or by an alkyl, alkoxy, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino or trifluoromethyl group,
to their enantiomers and diastereoisomers, and to addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that:
the term xe2x80x9calkylxe2x80x9d denotes a linear or branched hydrocarbon chain containing from 1 to 6 carbon atoms,
the term xe2x80x9calkoxyxe2x80x9d denotes a linear or branched alkyl-oxy group containing from 1 to 6 carbon atoms.
Among the pharmaceutically acceptable acids there may be mentioned hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are those wherein R1 and R2 together form a benzo ring which is unsubstituted or substituted by a group selected from methoxy and cyano, and R3 represents a hydrogen atom.
Among the preferred compounds of the invention there may be mentioned, more especially, N-(3-pyridyl)-1,2-dihydro-3H-benzo[e]indole-3-carboxamide, 7-methoxy-N-(3-pyridyl)-1,2-dihydro-3H-benzo[e]indole-3-carboxamide, 6-cyano-N-(3-pyridyl)-1,2-dihydro-3H-benzo[e]indole-3-carboxamide and N-(3-pyridyl)-2,3-dihydro-1H-benzo[f]-indole-1-carboxamide.
The present invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material a benzoindole of formula (II) 
wherein R1, R2 and R3 are as defined for formula (I),
which is condensed, under the action of heat, with a compound of formula (III): 
wherein Y represents a group xe2x80x94Nxe2x95x90Cxe2x95x90O or xe2x80x94C(O)xe2x80x94N3, to yield the compound of formula (I),
which may be purified, if necessary, according to a conventional purification technique,
which is separated, if desired, into its isomers (diastereoisomers and enantiomers) by a conventional separation technique,
which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that the indoline of formula (II) is prepared according to known procedures, for example starting from the corresponding nitronaphthylacetonitrile compound.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal or transdermal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels etc.
The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder, and also the administration route, which may be oral, nasal, rectal or parenteral. The unit dose generally ranges from 0.05 to 500 mg per 24 hours for treatment in 1 to 3 administrations.
The examples that follows illustrate, but do not limit, the invention.
The structures of the compounds described have been determined by conventional spectroscopic and spectrometric techniques.
The starting materials used are known products or are prepared according to known procedures.
Preparation 1:
Step A: (2-Nitro-1-naphthyl)acetonitrile
Prepare a solution of 53.5 g (0.477 mol) of potassium tert.-butanolate in 400 ml of dimethylformamide. Cool the resulting solution to xe2x88x9210xc2x0 C. and add thereto, over the course of about 1 hour, a solution of 40 g of 4-chlorophenoxyacetonitrile (0.24 mol) and 37 g of 2-nitronaphthalene (0.213 mol) in 200 ml of dimethylformamide. After 2 hours at xe2x88x925xc2x0 C., pour the mixture into 4 liters of water containing 1 liter of concentrated hydrochloric acid and extract the aqueous phase with 3xc3x97500 ml of dichloromethane. Wash the organic phase with 300 ml of water, dry it over magnesium sulphate, filter and then evaporate off the solvent.
65 g of product are obtained.
Recrystallise that 65 g from a mixture of cyclohexane/ethyl acetate: 50/50.
Step B: 3H-Benzofelindole
At ambient temperature and under 4 bars of hydrogen, hydrogenate 33 g of (2-nitro-1-naphthyl)acetonitrile (0.155 mol) dissolved in 630 ml of ethanol containing 10% water and 6.3 ml of pure acetic acid, using 19 g of 10% palladium-on-carbon. After absorption has ceased, filter off the catalyst, concentrate the solvent in vacuo and then take up the residue in 250 ml of dichloromethane; wash the organic phase with 100 ml of 0.1N potassium hydroxide solution and then dry the organic phase over magnesium sulphate, filter and concentrate.
The residue is purified by chromatography over silica, the eluant being cyclohexane/ethyl acetate: 80/20.
Step C: 2,3-Dihydro-1H-benzo[e]indole
10 g (0.06 mol) of the compound prepared in the previous step are dissolved in 50 ml of tetrahydrofuran. To the resulting solution, at 0xc2x0 C., add 120 ml of borane/THF complex as a 1M solution in tetrahydrofuran, and then 120 ml of trifluoroacetic acid. After 30 minutes, add, at 0xc2x0 C., 6 ml of water, stir for 15 minutes and then concentrate the mixture to dryness. The residue is taken up in 200 ml of dichloromethane and washed with 200 ml of IN sodium hydroxide solution. The organic phase is dried over magnesium sulphate, filtered and concentrated.
Preparation 2: 2,3-Dihydro-1H-benzo[f]indole
The experiment protocol for reducing 1H-benzo[f]indole is the same as that of Preparation 1, Step C. Synthesis of the starting material 1H-benzo[f]indole has been described in the literature [Tetrahedron, 49, 33, 7353 (1993); Heterocycles, 24, 7, 1845, (1986)].
Preparation 3: 2,3-Dihydro-1H-benzo[e]indole-6-carbonitrile
Step A: N-(5-Cyano-2-naphthyl)acetamide
To 25 g of N-(5,6,7,8-tetrahydronaphth-2-yl)acetamide cooled to 0xc2x0 C. add, successively, 70 ml of pure trimethylsilyl cyanide and then 30 g of dichlorodicyanoquinone in 70 ml of dichloromethane. After 3 hours at ambient temperature, again add a solution of 60 g of dichlorodicyanoquinone in 140 ml of dichloromethane. Stir at 20xc2x0 C. for 12 hours and then heat at 60xc2x0 C. for 8 hours.
After neutralising with saturated sodium hydrogen carbonate solution, the organic phase is separated off and washed with water. The residue obtained after concentration is purified by chromatography over silica gel using a mixture of cyclohexane/ethyl acetate: 80/20 as eluant.
Step B : N-(1-Bromo-5-cyano-2-naphthyl)acetamide
To a solution, cooled to xe2x88x925xc2x0 C., of 50 g (0.238 mol) of the product synthesised in the previous step in 500 ml of dichloromethane and 25 ml of pyridine, add 39.8 g of bromine dissolved in 200 ml of dichloromethane. Then stir vigorously for 4 hours at ambient temperature; subsequently dilute with 500 ml of dichloromethane, wash the organic phase twice with 300 ml of water, dry and concentrate. The residue is recrystallised from a mixture of dichloromethane/methanol: 50/50.
Step C: 6-Amino-5-bromo-1-naphthonitrile
Heat at 80xc2x0 C., for 6 hours, a mixture of 12.5 g (0.043 mol) of the product synthesised in the previous step, 3.6 g of sodium hydroxide, 195 ml of methanol and 65 ml of water. After evaporating off the methanol, the aqueous phase is extracted twice with dichloromethane. The latter is subsequently dried and evaporated off. The residue is crystallised from a dichloromethane/methanol mixture.
Step D: Ethyl 1-bromo-5-cyano-2-naphthylcarbamate
Add, at 0xc2x0 C., 19 ml of ethyl chloroformate to a solution of 33 g (0.133 mol) of the product synthesised in the previous step in 200 ml of pyridine. After 1 hour at 5xc2x0 C., evaporate off the solvent, take up the residue in 500 ml of dichloromethane, wash the organic phase 3 times with 100 ml of 0.1N hydrochloric acid and then with 200 ml of 10% sodium hydrogen carbonate solution and finally once with water. The residue obtained by evaporation is recrystallised from a dichloromethane/methanol mixture.
Step E: Ethyl 5-cyano-1-[(trimethylsilyl)ethynyl]-2-naphthylcarbamate
In a steel reactor, mix 14.1 g (0.044 mol) of the product synthesised in the previous step, 11 ml of trimethylsilylacetylene, 13 ml of triethylamine, 670 mg of cuprous iodide and 1.54 g of dichloro-bis(triphenylphosphine)palladium. Then close the reactor and heat the reaction mixture at 80xc2x0 C. for 4 hours. Dilute with 200 ml of dichloromethane and 100 ml of water, filter the mixture, separate off the organic phase, dry it and evaporate off the solvent in vacuo. The residue obtained is purified by chromatography over silica gel using a mixture of cyclohexane/ethyl acetate: 90/10 as eluant, followed by crystallisation from the same solvent.
Step F: 3H-benzo[e]indole-6-carbonitrile
To a solution of 2.74 g of sodium in 280 ml of dry ethanol add 10 g (0.0297 mol) of the product synthesised in the previous step and heat the mixture at reflux for one hour. After evaporating off the solvent, the residue is taken up in 200 ml of dichloromethane and the organic phase is washed with 200 ml of water. After evaporation, the residue is purified by chromatography over silica gel using a mixture of cyclohexane/ethyl acetate: 80/20 as eluant.
Step G: 2,3-Dihydro-1H-benzo[e]indole-6-carbonitrile
The experiment protocol for reducing 3H-benzo[e]indole-6-carbonitrile is the same as that of Preparation 1, Step C.
Preparation 4: 7-Methoxy-2,3-dihydro-1H-benzo[e]indole
Step A : 6-Methoxy-3,4-dihydro-1(2H)-naphthalenone oxime
Dissolve 100 g (0.57 mol) of 6-methoxy-1-tetralone in 2.5 liters of a mixture of ethanol/water: 80/20. There are then added, at ambient temperature, 85 g (1.04 mol) of sodium acetate and 43 g (0.62 mol) of hydroxylamine hydrochloride. Heat the suspension at reflux for 4 hours. Dilute the mixture with 5 liters of water and extract with ethyl ether, wash with water, dry over magnesium sulphate and filter. After evaporating off the solvent, 99 g of a beige solid are obtained.
Step B: 2-Amino-6-methoxy-3,4-dihydro-1(2H)-naphthalenone
Dissolve 50 g (0.26 mol) of the product synthesised in the previous step in 185 ml of pyridine and then add, at ambient temperature, 54.9 g (0.29 mol) of para-toluenesulphonyl chloride. After 24 hours, pour onto ice and then filter off the precipitate. Take up the precipitate in dichloromethane and wash with water; dry the organic phase over magnesium sulphate and filter. After evaporating off the solvent, 89 g of a yellow solid (intermediate product 1) are obtained.
Add 7.48 g (0.32 mol) of sodium to a mixture of toluene/ethanol: 720/148 ml. After dissolution, dilute with 940 ml of toluene and rapidly add 117 g (0.34 mol) of intermediate product 1. After 24 hours at ambient temperature, filter off the sodium para-toluenesulphonate, rinse with toluene, and then pour the organic solution into 10% hydrochloric acid solution (1.1 liters). Separate off, extract once with water and then evaporate the aqueous phase. Take up the residue in ethanol and then filter off the precipitate. 46.5 g of a beige solid in the form of the hydrochloride are obtained.
Step C: N-Ethyl-Nxe2x80x2-(6-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthyl)urea
Pour 4.77 g (0.044 mol) of ethyl chloroformate at 0xc2x0 C. into 5 g (0.022 mol) of 2-amino-6-methoxy-3,4-dihydro-2H-naphthalen-1-one dissolved in pyridine. After two hours at ambient temperature, concentrate the pyridine, take up in dichloromethane and then wash the organic phase with 0.1N hydrochloric acid solution and then with saturated sodium hydrogen carbonate solution and water; dry over magnesium sulphate, filter, and evaporate off the solvent. 5.48 g of an orange solid are obtained.
Step D: N-Ethyl-Nxe2x80x2-(6-methoxy-1,2,3,4-tetrahydro-2-naphthyl)urea
At 60xc2x0 C. and under atmospheric pressure, hydrogenate 98 g (0.37 mol) of the product previously prepared in Step C and dissolved in 1.5 liters of ethanol, using 10 g of 5% palladium-on-carbon. After the absorption has ceased, filter off the catalyst and concentrate the solvent in vacuo. 88.2 g of an oil are obtained.
Step E: N-Ethyl-Nxe2x80x2-(6-methoxy-2-naphthyl)urea
Dissolve 7.42 g (0.0298 mol) of the product synthesised in the previous step in 100 ml of toluene. Add 13.51 g (0.0595 mol) of dichlorodicyanoquinone and heat at reflux for 30 minutes. Filter off the precipitate at ambient temperature, rinse with toluene and then evaporate off the solvent. The residue is purified by chromatography over silica gel using pure dichloromethane as eluant. 4 g of a grey solid are obtained.
Step F: 6-Methoxy-2-naphthylamine
Dissolve 3.5 g of the product synthesised in the previous step in 65 ml of ethanol and then add a solution of potassium hydroxide in 65 ml of water. After refluxing for 4 hours, filter off, at ambient temperature, the precipitate that is formed. Take up the crude product in dichloromethane and wash with water until neutral; dry over magnesium sulphate, filter off the precipitate and then evaporate off the solvent. 2.02 g of an orange solid are obtained.
Step G: 1-Iodo-6-methoxy-2-naphthylamine
28.2 g (0.16 mol) of the product synthesised in the previous step are dissolved in a mixture of dichloromethane/methanol: 1500/620 ml. To the resulting solution add, at ambient temperature, 56.7 g (0.16 mol) of benzyltrimethylammonium dichloroiodate and 21.2 g (0.212 mol) of calcium carbonate. After 30 minutes, filter off the insoluble material, then take up the organic phase with 10% sodium bisulphite solution and extract with ethyl ether. Dry over magnesium sulphate, filter and evaporate. The residue is purified by chromatography over silica gel, using a mixture of cyclohexane/ethyl acetate: 70/30 as eluant.
Step H: Ethyl 1-iodo-6-methoxy-2-naphthylcarbamate
Conversion of 1-iodo-6-methoxy-2-naphthylamine is carried out by applying the method described in Preparation 3, Step D.
Step I: Ethyl 6-methoxy-1-[(trimethylsilyl)ethynyl]-2-naphthylcarbamate
Conversion of ethyl 1-iodo-6-methoxy-2-naphthylcarbamate is carried out by applying the method described in Preparation 3, Step E.
Step J: 7-Methoxy-3H-benzo[e]indole
Conversion of the compound of the previous step is carried out by applying the method described in Preparation 3, Step F.
Step K: 7-Methoxy-2,3-dihydro-1H-benzo[e]indole
The experiment protocol for reducing 7-methoxy-3H-benzo[e]indole is the same as that of Preparation 1, Step C.